Following Ambassador Udina's compliant to the Council accusing Saren of attacking the human colony of Eden Prime, Garrus was placed in charge of a C-Sec investigation into the matter. This task proved difficult, as Saren still retained the rank of a Spectre, meaning that all of his files were classified. Due to this, Garrus was unable to gain any solid evidence or Saren's activities. Garrus pleaded with Executive Pallin to extend the time limit placed on the investigation. Pallin, however, believed that no significant evidence had been found to justify adding more time, and so called the investigation off. Garrus decided to follow his final lead, which brought him to the Med Clinic in the Wards.

During Shepard's own investigation into Saren, it is suggested that he seek the aid of Garrus. Shepard met with a suspended C-Sec officer named Harkin, who told him that Garrus was planning to attack a group of thugs in the Med Clinic. Shepard arrived in time to see Dr. Chloe Michel being held at gun point by the thugs. Garrus was hiding in the shadows, ready to attack. As Shepard moves in closer to the thugs, Garrus shoots their leader, free Dr. Michel. Following the shootout, Garrus tells Shepard that he is leaving C-Sec. He wants to stop Saren, believing him to be guilt of all accusations. He asks Shepard to join his team. Shepard agrees and Garrus becomes part of the Normandy's crew.

Garrus is a calm and reassuring person, who is courteous outside of combat, and ruthless during a fight. Garrus believes that the Normandy is impressive, saying that she is the proof that the Turians and Humans can accomplish great things together. He is eager to see how capable the Normandy is in combat, believing it to be able to do serious damage thanks to its stealth capabilities. Despite Ashley's cautious attitude of allowing aliens free access to the ship, Garrus gets along well with the crew. He enjoys the opportunity to meet new people outside of the Citadel. He is surprised by Wrex, beveling all Krogan to be violent thugs. This causes Wrex to reply; "What, using the genophage was more bearable when all krogan were savage thugs? You'd better head back to the ship, kid – any longer out here in the real world and you just might have to learn something."

Garrus reveals little of his past, other than the fact that he grew up on the planet Palaven. He tells Shepard of his father, whom was a strict by-the-book C-Sec investigator. Garrus claims he was one of the best, following the belief of "Do things right or don't do them at all." Garrus tells Shepard that he was a potential Spectre candidate, although he was selected along with a thousand other Turians. His father prevented him from receiving special Spectre training, despising the freedom Spectres have over the law. He claims that his father wouldn't like Shepard. Garrus doesn't seem to show any regret over not becoming a Spectre, but is interested in seeing how they complete their jobs. He believes Saren to be a disgrace to the Turian species, which is part of the reason he wants to stop him.

Harkin believes Garrus a fool, describing him as a hothead "still thinks he can change the world." He was always arguing with Executor Pallin. the Executor believes him to be a great investigator, but claims that he should be more considerate of the law. Garrus believes C-Sec is too strict with their rules. He particularly dislikes it when suspects are given their freedom due to the heavy regulations. "still thinks he can change the world," can offer his opinion on this matter. Garrus is concerned with how the Council will treat Saren once apprehended. He believes that Saren will either escape or the Council will protect him to prevent any political blow-back. Garrus suggests that they kill Saren outright, rather than handing him over to the Council. Again, Shepard can offer his opinion on the matter.

Garrus eventually thanks Shepard for allowing him the opportunity to work with the Normandy crew. Garrus tells Shepard that he has learned a great deal working under Shepard's wing. Depending on the guidance Shepard has given him throughout the game, Garrus claims that he is going to reapply for Spectre training. Either with or without being re-instated in C-Sec.

Through a conversation with Garrus, he will tell Shepard of a gruesome case he once encountered will working for C-Sec. Garrus recalls an investigation into a Salraian, Dr. Saleon. The Doctor had been growing organs inside living people, then farming them when they were in full working order. Saleon was able to escape the Citadel with a number of hostages because the Citadel authorities refused to destroy his ship. This enraged Garrus who believed that the hostage were now living in a world of pain as his test subjects. This caused Garrus to rethink his beliefs of C-Sec.

Garrus has acquired the co-ordinates to Dr. Saleon's ship. Shepard can then track down the doctor to help give Garrus closure. Dr. Saleon has changed his name to Dr. Heart, which Garrus believes is his idea of a joke. Shepard can either allow Garrus to kill Dr. Heart, or tell him that the doctor will suffer more if placed in prison. In this case, Dr. Heart resists arrest and forces Shepard to kill him. Afterwards, Garrus thanks Shepard for his help and returns to the mission at hand.

After hearing of the destruction of the Normandy, Garrus moved to Omega to tackle the crime, free from the restrictions of C-Sec. Garrus began to cause disruption for the three major Mercenary groups of Omega; the Blue Suns, Blood Pack and the Eclipse. Garrus gained a reputation for himself, earning the nickname Archangel, an alias given to him by the resident of Omega who were thankful for him bringing justice to the criminals. Garrus was bale to recruit a team of twelve other operatives, from various backgrounds. Some where ex C-sec like himself, others were from military and some grew up on Omega. They all had one thing in common; they lost someone to the gangs of Omega. His actions have caused a lot of misery for the Mercenaries. They formed a temporary alliance in an attempt to eradicate Garrus and his team. These Mercenaries were never seen to act together unless there was a war. Garrus was smart enough not disrupt the operations of Aria T'Loak.

When Shepard arrives on Omega to recruit Archangel, he finds that he is surrounded at his base of operations by the Mercenaries, who have a plan to final kill Archangel. The Mercs are recruiting freelancers as cannon fodder to draw Archangel's attention while they work to get an infiltration team under the building complex for a surprise attack. Shepard is recruited as a freelancer in an attempt to meet with Archangel. When crossing the bridge to reach Archangels position, Shepard turns on the other freelancers, killing them. When Shepard gets through to Archangel, he removes his helmet, revealing himself as Garrus. He explains to Shepard that he formed his own team, much like Shepard to combat the crime on Omega. After explaining the situation, Shepard assists Garrus in taking out the Mercenaries, killing their leaders in the process. The leader of the Blue Suns, Tarak, attacks the base with a gunship, brutally wounding Garrus in the process. Following the battle, Shepard rushes Garrus back to the Normandy to receive urgent medical treatment.

Dr. Chakwas is able to treat Garrus's wounds, but she in unable to completely repair the damage. Garrus enters the Comm room, showing of a multitude of heavy scars along the right side of his face. His face has been repaired with bandages and artificial grafting. Jacob tells Shepard that cybernetic implants were required to keep Garrus alive. Garrus also suffered damage to his upper torso. His armor bears the damage of the gunship attack.

Following the events on Omega, it becomes apparent that Garrus has changed and has become even more disconnected with life. Regardless of the guidance he received from Shepard two years previous, Garrus is unable to withstand the bureaucracy of the Citadel. Garrus showed great disdain for the Council after their attempt to disregard Sovereign's attack as the first stage of a Reaper invasion. After hearing of Shepard's death, Garrus quickly left the Citadel to deal with crime following his own initiative. He quickly moved to Omega. He reveals to Shepard that he gained a team in a similar way to Shepard, claiming that if you can get things done people will become interested. After losing his team due to a traitor, Garrus became overwhelmed with anger and guilt, leading him to become violent. Garrus jokes with Shepard that he isn't a very good Turian, seeing as he lacks the discipline to follow pointless orders. He believes that with the threat of the Reapers, it is not worth blindly following bad orders.

Following the deaths of his team, Garrus believes that Shepard is the only friend that he has left in the galaxy.

Garrus is a potential romance for female Shepard's after the completion of his Loyalty mission. From the outset, Garrus is awkward in the relationship. If Shepard asks if he is uncomfortable with the idea, Garrus responds that he is just nervous and that Shepard never has to worry about making him uncomfortable. Garrus tells Shepard that he feels alone in the galaxy, believing Shepard to be his only friend. Garrus says that he isn't interested in humans, just Shepard. Before heading to the Omega-4 Relay, Garrus reveals that he wants "something to go right, just once." Garrus refers to his failed work at C-Sec and the deaths of his team at the hands of Sidonis. Shepard then touches his face, with the scene blacking out after the two touching foreheads.

Garrus is a potential romance for a female Shepard. The option becomes available after completing Garrus' loyalty mission. As the romance begins, Garrus' demeanor is somewhat awkward; nevertheless, if Shepard asks Garrus whether his behavior suggests that he is uncomfortable with the idea, Garrus says he is just nervous, and that Shepard never has to worry about making him uncomfortable. In these more vulnerable moments, Garrus admits he feels very alone in the galaxy, considering Shepard the only friend he has left. During the final scene, Garrus confesses he wants "something to go right" (he mentions Sidonis and his work with C-Sec as times where he failed, implying his departure form C-Sec may not have been entirely his choice) after which Shepard—who slowly approaches him while he talks—touches his face, stroking the scar he gained during his recruitment mission. The scene ends with the two of them touching foreheads affectionately, followed by Garrus reaching up as though to touch Shepard's shoulder before the scene fades to black.